This is a Phase I SBIR Application entitled Novel Inhibitors of Multi-Drug-Resistant Mutants of BCR- ABL for the Treatment of Chronic Myelogenous Leukemia (CML) and Ph+ Acute Lymphocytic Leukemia (ALL). The overall goal of this proposal is to further optimize and improve the efficacy of novel classes of compounds discovered, developed and patented by HPRL, using a mouse model of leukemia. A secondary goal is to further optimize two or three of the best lead candidates for cellular specificity and oal bioavailability. All of the HPRL compounds relevant to this proposal are nanomolar inhibitors of the T315I mutant of the BCR- ABL oncogene product, an oncoprotein which is of central importance in the development of chronic myelogenous leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL). The NIH support will be used to focus research at Housey Pharmaceutical Research Laboratories (hereinafter HPRL) to further develop and commercialize discoveries originally made in the laboratories of Dr. Charles Sawyers, M.D., when his laboratory was located at the University of California at Los Angeles (UCLA), Los Angeles, CA. These discoveries have been exclusively licensed by UCLA to HPRL for therapeutic applications. This Phase I proposal builds upon the solid scientific foundation established by Dr. Sawyers and his colleagues while at UCLA. Dr. Sawyers is now the Chairman of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center and serves as HPRL's Principal Scientific Advisory Board member and Senior Consultant with respect to this therapeutic program. Over the past eight years, Dr. Sawyers and his colleagues, including Dr. Neil Shah, M.D., also an HPRL consultant and now at University of California at San Francisco (UCSF), have made seminal discoveries surrounding the development of resistance to imatinib mesylate (Gleevec), a medicine which has revolutionized the treatment of chronic myelogenous leukemia (CML). They have also made key contributions to the development of dasatinib (Sprycel), a compound which is capable of treating some, but not all, of the BCR-ABL mutations that emerge in CML patients who eventually develop imatinib resistance. The proposal provides the unique opportunity to further develop and commercialize key intellectual property and technology originally created by NIH-supported scientists at the University of California at Los Angeles (UCLA), the Memorial Sloan Kettering Cancer Center (MSKCC), and the University of California at San Francisco (UCSF) who are acknowledged leaders in the field. The proposal brings together the academic expertise of leaders in the field of imatinib resistance with Housey Pharmaceutical Research Laboratories (HPRL), an organization whose scientists have a strong track record of creating, developing and commercializing intellectual property and technology of formidable market value. Cell-based assay technology originally developed by Housey scientists has been licensed and is being utilized by the majority of the world's best research-based pharmaceutical concerns. In this field, both Novartis and Ariad have already sublicensed certain BCR-ABL-related Intellectual Property from HPRL, independently validating the caliber of the technology. Other licenses are anticipated in the near future. Strong Letters of support from Dr. Ragab, Vice President of Oncology, Search and Evaluation at Bristol Myers Squibb as well as Dr. Sawyers, who is also a Member of the Board of Directors at Novartis, highlight the overall enthusiasm for this project and underscore the importance of successfully addressing this urgent unmet medical need.